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Kinetic Evaluation of Human Cloned Coproporphyrinogen Oxidase Using a Ring Isomer of the Natural Substrate Marjorie A

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Kinetic Evaluation of Human Cloned Coproporphyrinogen Oxidase Using a Ring Isomer of the Natural Substrate Marjorie A View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by ISU ReD: Research and eData Illinois State University ISU ReD: Research and eData Faculty Publications – Chemistry Chemistry 11-1-2005 Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate Marjorie A. Jones Illinois State University Christopher L. Cooper Illinois State University Timothy D. Lash Illinois State University Follow this and additional works at: http://ir.library.illinoisstate.edu/fpchem Part of the Condensed Matter Physics Commons Recommended Citation Jones, Marjorie A.; Cooper, Christopher L.; and Lash, Timothy D., "Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate" (2005). Faculty Publications – Chemistry. Paper 1. http://ir.library.illinoisstate.edu/fpchem/1 This Article is brought to you for free and open access by the Chemistry at ISU ReD: Research and eData. It has been accepted for inclusion in Faculty Publications – Chemistry by an authorized administrator of ISU ReD: Research and eData. For more information, please contact [email protected]. Illinois State University ISU ReD: Research and eData Chemistry Department Arts and Sciences 11-1-2005 Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate Marjorie A. Jones Illinois State University Christopher L. Cooper Illinois State University Timothy D. Lash Illinois State University Follow this and additional works at: http://ir.library.illinoisstate.edu/chem Part of the Chemistry Commons Recommended Citation Jones, Marjorie A.; Cooper, Christopher L.; and Lash, Timothy D., "Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate" (2005). Chemistry Department. Paper 3. http://ir.library.illinoisstate.edu/chem/3 This Article is brought to you for free and open access by the Arts and Sciences at ISU ReD: Research and eData. It has been accepted for inclusion in Chemistry Department by an authorized administrator of ISU ReD: Research and eData. For more information, please contact [email protected]. © Med Sci Monit, 2005; 11(11): BR420-425 WWW.MEDSCIMONIT.COM PMID: 16258391 Basic Research Received: 2005.06.28 Accepted: 2005.08.08 Kinetic evaluation of human cloned coproporphyrinogen Published: 2005.11.01 oxidase using a ring isomer of the natural substrate Authors’ Contribution: Christopher L. CooperABCDEFG, Timothy D. LashABCDEFG, Marjorie A. JonesABCDEFG A Study Design B Data Collection Department of Chemistry, Illinois State University, Normal, IL, U.S.A. C Statistical Analysis D Data Interpretation Source of support: This work was supported in part by a grant from Sigma Xi: The Scientifi c Research Society E Manuscript Preparation and by the Illinois State University Honors Program Undergraduate Research Scholarship (CLC) and NIH # 1 R15 F Literature Search GM/OD/52687-01A1 G Funds Collection Summary Background: The enzyme coproporphyrinogen oxidase (copro’gen oxidase) converts coproporphyrinogen-III (C-III) to protoporphyrinogen-IX via an intermediary monovinyl porphyrinogen. The A ring iso- mer coproporphyrinogen-IV (C-IV) has previously been shown to be a substrate for copro’gen ox- idase derived from avian erythrocytes. In contrast to the authentic substrate (C-III) where only a small amount of the monovinyl intermediate is detected, C-IV gives rise to a monovinyl interme- diate that accumulates before being converted to an isomer of protoporphyrinogen-IX. No kinet- ic studies have been carried out using the purifi ed human copro’gen oxidase to evaluate its abili- ty to process both the authentic substrate as well as analogs. Materials/Methods: Therefore, purifi ed, cloned human copro’gen oxidase was incubated with C-III or C-IV at 37oC with various substrate concentrations (from 0.005 µM to 3.5 µM). The Km (an indication of mo- lecular recognition) and Kcat (turnover number) values were determined. Results: The Km value for total product formation was about the same with either C-III or C-IV indicating the same molecular recognition. However, the catalytic effi ciency (Kcat/Km) of the enzyme for to- tal product formation was not more than two fold higher using C-III relative to C-IV. Conclusions: Since the Km values are about the same for either substrate and the total Kcat/Km values are within two fold of each other, this could correlate with the increase of severity of porphyrias with monovi- nyl accumulation. The ability of the increased levels of C-IV to compete with the authentic sub- strate has important implications for clinical porphyrias. key words:EDUCATIONAL coproporphyrinogen oxidase • porphyria • Km • Kcat • substrate analog USE Full-text PDF: http://www.medscimonit.com/fulltxt.php?IDMAN=7723 Word count: 2471 Tables: 1 Figures: 5 References: 17 Author’s address: Marjorie A. Jones, Department of Chemistry, Illinois State University, Normal, IL 61790-4160, U.S.A., e-mail: [email protected] BR420 Current Contents/Clinical Medicine • SCI Expanded • ISI Alerting System • Index Medicus/MEDLINE • EMBASE/Excerpta Medica • Chemical Abstracts • Index Copernicus Electronic PDF security powered by ISL-science.com This copy is for educational use only - distribution prohibited. Med Sci Monit, 2005; 11(11): BR420-425 Cooper CL et al – An a ring isomer as substrate for coproporphyrinogen oxidase BACKGROUND with the correct sequence of substituents for the second “B ring” propionate group to undergo oxidative decarboxyla- Porphyrias are a group of clinical disorders, either genet- tion. The Lash et al. paper also models the active site with ic or acquired, that are characterized by accumulation of C-IV leaving the active site and re-entering prior to the sec- BR one or more type of porphyrins in tissues as well as high- ond oxidative decarboxylation [11]. This isomer of the au- er levels of excretion in the urine and/or feces. These thentic substrate has the sequence of the methyl and pro- patients are generally characterized with mild to severe pionate groups on ring A switched, giving the molecule a mental retardation, photosensitivity, and problems in plane of symmetry that is absent in C-III, and also provid- the liver and/or bone marrow. Thus, understanding the ing two sequences of substituents that can be recognized at enzymes involved in the heme biosynthesis pathway and the active site. However, the active site model predicts that their ability to process both the authentic substrates and once the fi rst oxidative decarboxylation has occurred, the analogs of these substrates is important in helping to devel- second propionate side chain cannot be correctly orientat- op clinical therapies for porphyrias. Defects in the various ed until the intermediate has dissociated from the bind- enzymes of the synthetic pathway have been correlated with ing pocket, fl ipped over, and reentered into the active site. various classes of porphyrias but much work yet remains. This prediction provided a tentative explanation for the differences in the observed kinetics using both substrates Coproporphyrinogen oxidase (copro’gen oxidase; EC by Jackson et al. [4]. Since C-IV can be processed as a sub- 1.3.3.3) is the sixth enzyme in the biosynthetic pathway for strate by normal (wildtype) copro’gen oxidase, this would the production of heme. Coproporphyrinogen-III (C-III), result in a divinyl product with a concomitant accumula- the authentic substrate for the enzyme copro’gen oxidase, tion of a monovinyl species. We speculate that the accumu- undergoes two sequential oxidative decarboxylations at the lation of both the mono- and divinyl products from C-IV A and B ring propionates to produce fi rst a monovinyl prod- in the mitochondria could then be correlated with clinical uct and then a divinyl product (Figure 1A). symptoms of the patients with harderoporphyria, resulting from the defect in a previous enzyme rather than in the Harderoporphyria is a disorder often characterized by an copro’gen oxidase enzyme. However, the active site model accumulation of monovinyl porphyrins in the body and was designed from results observed using crude preparations considered to be related to mutations in the gene encod- of copro’gen oxidase from avian erythrocytes. As yet there ing copro’gen oxidase. In addition, C-III and its isomer co- have been no reports on the kinetics for C-IV metabolism proporphyrinogen-IV (C-IV) have been isolated from these using highly purifi ed human enzyme preparations. In this types of patients [1]. Yet, C-IV also has been reported in the work, experiments were performed using purifi ed prepara- urine of patients with a defect in the enzyme 5-aminolevulin- tions of the cloned human enzyme. The kinetic constants ic acid dehydratase [2]. Kühnel et al. [1] also reported the (Km, Kcat, and Kcat/Km) were determined using non-lin- presence of C-IV in the urine of normal people, although ear regression under initial velocity (vo) conditions using in much lower amounts. either C-III or C-IV as substrate. Modifi ed porphyrinogens have been used to probe the ac- MATERIAL AND METHODS tive site of copro’gen oxidase. C-IV was fi rst found to be a substrate for ox-liver copro’gen oxidase by Porra and Falk Coproporphyrin-IV tetramethyl ester was prepared by the in 1964 [3], and was subsequently shown to be converted cyclization of an a,c-biladiene intermediate following the to protoporphyrinogen-XIII via a monovinyl intermediate method reported by Lash et al. [10] and coproporphyrin (Figure 1B). Jackson et al., using crude enzyme preparations III tetramethyl ester was purchased from Aldrich Chemical from chicken red blood cells, reported that the monovinyl Company. Prior to reduction to the corresponding porphy- intermediate from C-IV accumulated to about 40% total rinogens, they were incubated overnight with 8.3 M HCl to porphyrinogen at intermediary incubation times, but was remove the methyl esters.
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